DCBLD2 gene variations correlate with nasal polyposis in Korean asthma patients.
ABSTRACT Nasal polyps are abnormal lesions that cause airway obstruction and can occur along with other respiratory diseases. On account of its association with aspirin exacerbated respiratory disease (AERD), the human discoidin, CUB and LCCL domain containing 2 (DCBLD2) is hypothesized to be a candidate gene for the development of nasal polyps in asthma patients.
A total of 12 single-nucleotide polymorphisms (SNPs) were genotyped in 467 Korean asthma patients who were stratified further into 108 AERD and 353 aspirin-tolerant asthma (ATA) subgroups. Five major haplotypes were inferred from pairwise comparison of the polymorphisms. The patients were matched to control for confounds, and differences in the frequency distribution of DCBLD2 SNPs and haplotypes were analyzed using logistic models via various modes of genetic inheritance.
Results reveal significant association of rs828618 and DCBLD2_ht1 with nasal polyposis in the overall asthma patients group (P = 0.006, P(corr) = 0.05). Interestingly, the strength of association were maintained in the ATA subgroup (P = 0.007, P(corr) = 0.06), and moderate correlation was detected in the AERD subgroup (P = 0.04-0.05, P(corr) > 0.05).
Although further replication and validation are needed, these findings suggest that DCBLD2 could be a potential marker and drug target for treatment of nasal polyposis in Korean asthma patients.
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ABSTRACT: The pathogenesis of nasal polyps in chronic rhinosinusitis is poorly understood. These studies seek to implicate a functional role for vascular endothelial growth factor (VEGF) in perpetuating primary nasal epithelial cell overgrowth, a key feature of hyperplastic polyps. Comparison of VEGF and receptor expression was assessed by ELISA of nasal lavage, immunohistochemistry of sinus tissue, flow cytometry of nasal epithelial cells, and ELISA of supernatants. VEGF-dependent cell growth and apoptosis were assessed with blocking antibodies to VEGF, their receptors, or small interfering RNA knockdown of neuropilin-1 by cell proliferation assays and flow cytometric binding of annexin V. VEGF protein was sevenfold higher in nasal lavage from patients with polyposis compared with control subjects (P < 0.001). We also report elevated expression of VEGF (P < 0.012), receptors VEGFR2 and phospho-VEGFR2 (both P < 0.04), and identification of VEGF coreceptor neuropilin-1 in these tissues. Nasal epithelial cells from patients with polyps demonstrated faster growth rates (P < 0.005). Exposure of cells to blocking antibodies against VEGF resulted in inhibition of cell growth (P < 0.05). VEGF receptor blockade required blockade of neuropilin-1 (P < 0.05) and resulted in increased apoptosis (P < 0.001) and inhibition of autocrine epithelial VEGF production (P < 0.05). These data demonstrate that VEGF is a novel biomarker for chronic rhinosinusitis with hyperplastic sinonasal polyposis that functions in an autocrine feed-forward manner to promote nasal epithelial cell growth and to inhibit apoptosis. These findings implicate a previously unrecognized and novel role of VEGF functioning through neuropilin-1 on nonneoplastic primary human airway epithelial cells, to amplify cell growth, contributing to exuberant hyperplastic polyposis.American Journal of Respiratory and Critical Care Medicine 09/2009; 180(11):1056-67. · 11.04 Impact Factor
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ABSTRACT: In this report, we describe a simple correction for multiple testing of single-nucleotide polymorphisms (SNPs) in linkage disequilibrium (LD) with each other, on the basis of the spectral decomposition (SpD) of matrices of pairwise LD between SNPs. This method provides a useful alternative to more computationally intensive permutation tests. A user-friendly interface (SNPSpD) for performing this correction is available online (http://genepi.qimr.edu.au/general/daleN/SNPSpD/). Additionally, output from SNPSpD includes eigenvalues, principal-component coefficients, and factor "loadings" after varimax rotation, enabling the selection of a subset of SNPs that optimize the information in a genomic region.The American Journal of Human Genetics 05/2004; 74(4):765-9. · 11.20 Impact Factor
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ABSTRACT: Semaphorins are newcomers to the growing panoply of immunoregulatory proteins. Members of this family were originally identified as proteins that provide axonal guidance cues during neuronal development. However, accumulating evidence indicates that several semaphorins, called 'immune semaphorins', are crucial to various phases of the immune response, from initiation to terminal inflammatory processes. Extensive studies of immune semaphorins have shown not only differences but also parallels in semaphorin functions among physiologically distinct systems, providing unexpected but meaningful insights into the biological activities of this protein family. Here we review the present knowledge of the function of semaphorins and their receptors in the immune system, including the most recent advances in this field.Nature Immunology 02/2008; 9(1):17-23. · 26.20 Impact Factor